Histamine is one of the biological amines broadly distributed in biological tissues. Its pharmacological activities are transferred into cells via histamine receptors existing on the cell surface. Histamine H1, H2 and H3 receptors have so far been known as the histamine receptors [Ash and Schild, Br. J. Pharmac. Chemother., vol. 27, pp. 427-439, 1966, Black et al., Nature, vol. 236, pp. 385-390, 1972, Arrang et al., Nature, vol. 302, pp. 832-837, 1983]. In addition, finding of H4 receptor has recently been reported [Oda et al., J. Biol. Chem., vol. 275, pp. 36781-36786, 2000], and various studies are still under progress on histamine receptors and ligands thereof.
Among them, it has been revealed that histamine H3 receptor regulates synthesis and release of histamine as an auto-receptor [Arrag et al., Neuroscience, vol. 15, pp. 533-561, 1985, Arrag et al., Neuroscience, vol. 23, pp. 149-157, 1978], and (R)-alpha-methylhistamine is known as a selective agonist, and thioperamide as an antagonist [Arrang et al., Nature, vol. 327, pp. 117-123, 1987]. In addition, it has been reported that histamine H3 receptor has a function as a hetero-receptor which controls release of serotonin, noradrenalin, dopamine and the like various neurotransmitters in the brain [Schlicker et al., Naunyn-Schmiedeberg's Arch. Pharmacol., vol. 337, pp. 588-590, 1988, Schlicker et al., Naunyn-Schmiedeberg's Arch. Pharmacol., vol. 340, pp. 633-638, 1989, Schlicker et al., J. Neural Transm., vol. 93, pp. 1-10, 1993]. In addition, it has been reported that histamine H3 receptor is also concerned in the release of norepinephrine and calcitonin gene-related peptide (CGRP) at the time of ischemia of heart muscle [Imamura et al., Circ. Res., vol. 78, pp. 475-481, 1996, Imamura et al., Circ. Res., vol. 78, pp. 863-869, 1996].
Several compounds have so far been found as histamine H3 receptor ligands, and their application to medicaments have been attempted. For example, in the case of GT-2331 as a histamine H3 receptor antagonist, clinical test is in progress now on attention-deficit hyperactivity disorder (ADHD) as the indication disease [Tozer and Kalindjian, Exp. Opin. Ther. Patents, vol. 10, pp. 1045-1055, 2000]. Also, a histamine H3 receptor agonist BP-2.94 is now under clinical test on asthma as the indication disease [Fozard, Curr. Opin. Investig. Drugs, vol. 1, pp. 86-89, 2000].
In addition to these, EP0531219A1 describes that histamine H3 receptor agonists can be expected to be applicable as an anti-migraine tranquilizer, sleep-inducer, an hypnotic, sedative, anxiolytic, anti-asthmatic and anti-inflammatory agent, notably for the bronchi, the skin or eyes, or as an anti-gastric ulcer agent, and the like. In addition, International Publication WO 2001/6865, International Publication WO 99/05115, International Publication WO 99/05141, International Publication WO 99/05141 and the like describe that it is possible to use histamine H3 receptor ligands as therapeutic agents for obesity, type II diabetes, epilepsy, sleep disorders, depression, Alzheimer disease and the like.
As an example of a histamine H3 receptor ligand screened from natural resources, verongamine isolated from a sponge has been reported [Mierzwa et al., J. Nat. Prod., vol. 57, pp. 175-177, 1994]. Including Verongamine, most of the conventional histamine H3 receptor ligands have imidazole ring, which is present in the structure of the endogenous ligand histamine. However, the PF1270A, B and C substances of the present application are novel histamine H3 receptor ligands which do not have the imidazole ring. Known microbial products structurally related to the compounds of the present invention include Marcfortine A which was reported for the treatment and prevention of parasitic diseases [Polonsky et al., J. Chem. Soc. Chem. Commun., pp. 601-602, 1980, U.S. Pat. No. 4,866,060], and the like. However, the compounds of the present application are novel substances whose structures are different from those of the already known compounds so far reported.
An object of the present invention is to provide novel histamine H3 receptor ligands useful for the treatment or prevention of various diseases in which histamine H3 receptor is concerned.